Concomitant TP53 mutations with response to crizotinib treatment in patients with ALK-rearranged non-small-cell lung cancer.

TP53 mutations are the most prevalent mutations detected in non-small-cell lung cancer (NSCLC) and have been revealed as a negative prognostic biomarker of outcome. The impact of concomitant TP53 mutations in ALK-rearranged NSCLC remains uncertain. Tumor samples from 64 ALK-rearranged NSCLC patients receiving crizotinib treatment were subjected to next-generation sequencing (NGS) to identify TP53 mutational status. The clinicopathologic features of the TP53 mutations and its impact on the effect of crizotinib treatment were analyzed. Among the 64 ALK-rearranged patients, 15 (23.4%) patients showed a TP53 mutation. Of these, six cases had disruptive mutations and nine with nondisruptive mutations. The objective response rate (ORR) and disease control rate (DCR) for TP53 mutated patients were both significantly lower compared with those for TP53 wild-type patients (p = 0.003 and 0.023, respectively). A significantly shorter progression-free survival (PFS) was found in TP53 mutated patients compared with TP53 wild-type patients (p = 0.045). Nondisruptive TP53 mutations were associated with a shorter PFS in comparison with disruptive TP53 mutations in ALK-rearranged patients (p = 0.069). When nondisruptive TP53 mutated patients were in comparison with TP53 wild-type patients, nondisruptive TP53 mutations were associated with a significant reduced PFS (p = 0.003). TP53 mutations, especially nondisruptive mutations, negatively affected the response to crizotinib and correlated with shorter PFS in ALK-rearranged NSCLC patients.

Song P ，Zhang F ，Li Y ，Yang G ，Li W ，Ying J ，Gao S ... -  《Cancer Medicine》

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer.

Kron A ，Alidousty C ，Scheffler M ，Merkelbach-Bruse S ，Seidel D ，Riedel R ，Ihle MA ，Michels S ，Nogova L ，Fassunke J ，Heydt C ，Kron F ，Ueckeroth F ，Serke M ，Krüger S ，Grohe C ，Koschel D ，Benedikter J ，Kaminsky B ，Schaaf B ，Braess J ，Sebastian M ，Kambartel KO ，Thomas R ，Zander T ，Schultheis AM ，Büttner R ，Wolf J ... -  《-》

Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants.

Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants. Our results indicate prolonged PFS in patients with EML4-ALK variant 2.

Li Y ，Zhang T ，Zhang J ，Li W ，Yuan P ，Xing P ，Zhang Z ，Chuai S ，Li J ，Ying J ... -  《-》

Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

In ALK-rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms. We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs. In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); P = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. ALK-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with nonfunctional p53. These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.

Tanimoto A ，Matsumoto S ，Takeuchi S ，Arai S ，Fukuda K ，Nishiyama A ，Yoh K ，Ikeda T ，Furuya N ，Nishino K ，Ohe Y ，Goto K ，Yano S ... -  《-》

Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes.

Tian P ，Liu Y ，Zeng H ，Tang Y ，Lizaso A ，Ye J ，Shao L ，Li Y ... -  《-》